Relaxin for treating patients afflicted of impaired glucose tolerance

a glucose tolerance and relaxin technology, applied in the field of relaxin for treating patients with impaired glucose tolerance, can solve the problem of not being able to specify the exact “effective amount” or “effective dose”, and achieve the effect of increasing patient compliance and therapeutic effect, preventing beta-cell loss, and reducing the rate of relaxin releas

Active Publication Date: 2015-02-05
IMMUNDIAGNOSTIK
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AI Technical Summary

Benefits of technology

[0018]In the composition for administration, the relaxin peptides are preferably compounded or adsorbed or encapsulated in a slow-release formulation for achieving therapeutically effective serum levels in the range from 100 to 5000 pg Rlx / ml, preferably from 500 to 1000 pg Rlx / ml for prolonged periods of time from one day to six months or even longer. Slow-release compositions ensuring therapeutically effective relaxin levels in serum from one to six months are preferred. The slow-release compositions may be based on a biodegradable matrix or hydrogel comprising polyesters capable of immobilizing relaxin and other water-soluble macromolecules. As the ester linkages cleave, the entrapped relaxin is gradually released into the surrounding environment and into circulation. The rate of hydrolysis and concomitant relaxin release can be controlled by constructing polyesters containing varying proportions of esters activated by electron-drawing substituents vicinal to the ester function and / or by varying cross linking. Such relaxin-containing hydrogels or matrixes may be fabricated as microspheres that can be suspended in isotonic solutions and passed through a hypodermic needle, e.g. an 18- or 22-gauge hypodermic needle. Other slow-release compositions may be formulated with adsorbents, namely cellulosic adsorbents, polymeric adsorbents, e.g. certain polyacrylonitriles (e.g. as produced by Mitsubishi Rayon Company Limited), immuno-adsorbents (cross linked polyvinyl alcohol gels) or activated carbon (product of Toyobo Co., Ltd.). Such forms of slow-release administration may help to increase the patient compliance and the therapeutic effect.
[0019]A preferred method of treatment comprises the administration of human relaxin to a person afflicted of impaired glucose tolerance or in risk of becoming afflicted of impaired glucose tolerance in a dosis to achieve relaxin levels of 100 to 5000 pg / ml in serum. The dose range is adjusted to offset the glucotoxic effects of high blood sugar on pancreas, namely insulin cells, beta cells and beta cell function, and to ensure regular insulin secretion to match the changing metabolic demands of the body. Thus, therapeutically effective relaxin levels in serum prevent loss of beta-cells and beta-cell function and have beneficial effects in the regulation of blood sugar levels if a person is at risk of dysglycaemia or suffering from insulin resistance and impaired glucose tolerance. The disclosure provides in the broadest sense pharmaceutical compositions comprising relaxin and a suitable pharmaceutical excipient or diluent for reducing the glucotoxic effects of blood sugar on the pancreas function, insulin cells, beta cells and beta cell function. Preferred embodiment relate to compositions for subcutaneous injection in a method of treatment of persons highly at risk of becoming afflicted of impaired glucose tolerance or already suffering from impaired glucose tolerance to ameliorate the toxic effects of high blood sugar and for ceasing the progress of the illness from a mild state of insulin resistance with or without impaired glucose tolerance to a manifest type-2 diabetes.

Problems solved by technology

Thus, it is not possible to specify an exact “effective amount” or “effective dose”.

Method used

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  • Relaxin for treating patients afflicted of impaired glucose tolerance
  • Relaxin for treating patients afflicted of impaired glucose tolerance
  • Relaxin for treating patients afflicted of impaired glucose tolerance

Examples

Experimental program
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Effect test

example 1

Effect of sc RIX on HOMA-Index in ZDF Rats

[0038]The homeostatic model assessment (HOMA=Insulin (μU / mi)×Glucose (mmol / l) / 22,5) allows a quantification of insulin resistance and beta-cell function on the basis of mathematical equations describing glucose regulation as a feedback loop (see Matthews DR at al. Diabetologia 1985; 28(7): 412-9); Turner RC et al, Metabolism 1985; 28 (11): 1086-96). In order to assess the effects of relaxin on a diabetic metabolism we determined the HOMA of 10-week old male Zucker Diabetic Fatty rats (#25) pre-, during and post subcutanous administration of porcine relaxin (500 μg / kg rat per day). Thus, we determined the glucose and insulin levels in serum of 25 ZDF rats prior and 48 hours after sc administration of porcine relaxin. This was completed by follow-up determinations of glucose and insulin concentrations in serum 48 hours post the termination of the administration of porcine relaxin. The respective results for the HOMA values are shown in FIGS. 1...

example 2

Effect of H2 RLX on HOMA-Index in Human Patients

[0040]In a study approved by the local ethical committee (Charité, Berlin, Germany) twelve patients (n=12) having type II diabetes or impaired glucose tolerance received intravenous synthetic H2 relaxin over a period of 16 hrs followed by a 24-hr follow-up . The anti-diabetic treatment of those patients was not varied. The improved HOMA-2 model used was in the present example because it reflects better human physiology. A HOMA of >2 indicates a potential insulin resistance; a HOMA of >2,5 beginning insulin resistance and a HOMA >5,0 is an average value of insulin resistance in untreated patients with manifest type-2 diabetes.

[0041]Of those twelve patients in this study two patients received sequential treatment for 8 hours each with dosages equivalent to 10 and 30μg / kg of subject body weight per day, 6 patients received sequential treatment with 240 and 480 μg / kg of subject body weight per day, and another 4 patients received a constan...

example 3

Influence of Sustained Glucose Concentration on the Function of Beta-Cells and Their Secretion of Insulin into the Supematant

[0043]In a further study we examined whether porcine relaxin has any effect on insulin expression and / or secretory capacity of pancreatic beta-cells. 2.5×105 rat insulinoma cells (INS-1 cells; see Mergler S et al, in Cellular Signalling (2008), doi: 10.1016 / j.cellsig.2008.08.015) were plated in a 24-well plate and grown for three days in RPMI-640 medium with supplements (Moore G. E. et. al., Culture of Normal Human Leukoctyes.” JAMA, v. 199, 519-524 (1967). On the day of the experiment, the medium was removed, and the INS-1 cells were washed three times and then preincubated for 30 min in KRB (Krebs-Ringer buffer: 115 mM NaCl, 5.9 mM KCl, 1.2 mM MgCl2, 1.2 mM NaH2PO4, 1.2 mM Na2PO4, 2.5 mM CaCl2, 25 mM NaHCO3, pH 7.4) comprising 0.5% BSA and 3.3 mM glucose. Cells were washed again with phosphate buffered saline (PBS: 137 mM NaCl, 2,7 mM KCl, 12 mM phosphate, p...

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Abstract

A pharmaceutical composition for treatment for of r afflicted or in risk of becoming of impaired glucose tolerance (IGT) and/or type-2 it comprising an effective amount of relaxin for protecting beta-cells and beta-cell function against the effects of high blood glucose (glucotoxicity). Treatment of persons of disglycaemias, and protection of beta cells of the islets of Langerhans and beta-cell function in patients having type-2 diabetes, is diclosed.

Description

FIELD OF THE INVENTION[0001]The present invention relates to pharmaceutical compositions and methods for treating human subjects in risk of becoming afflicted with impaired glucose tolerance (IGT).BACKGROUND OF THE INVENTION[0002]Diabetes mellitus is a group of metabolic diseases in which a person has high blood sugar (i. e. glucose), either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. The high blood sugar produces the classical symptoms of polyuria, polydipsia and polyphagia. There are three main types of diabetes: Type-1 diabetes results from the body's failure to produce insulin. Type-1 diabetes is also referred to as insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes. Type-2 diabetes results from a condition in which cells fall to use insulin properly or have become “resistant” to insulin. Insulin resistance (IR) in muscle and fat cells reduces glucose uptake and its local storage as glycogen or t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/22
CPCA61K38/2221A61K9/0019A61K9/1647A61P3/10
Inventor DSCHIETZIG, THOMAS
Owner IMMUNDIAGNOSTIK
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